The expression of ligands and receptors of the EGF supergene family was examined in the several stages of human ovarian carcinogenesis. Fourteen ovarian cystadenocarcinomas, 10 ovarian carcinomas of low malignant potential (borderline), and 20 ovarian cystadenomas were compared to 8 normal ovaries for immunoperoxidase detection of the ligands EGF, TGF-a, amphiregulin, cripto, and the receptors EGFR and c-erbB-2. Amphiregulin immunostaining was expressed principally in borderline tumors, and the possibility of antigenic masking in other tissue types is under evaluation. TGF-a differed most from EGF in the borderline tumors, in which EGF was uniformly positive while TGF-a was least frequently positive (60%). Cripto was observed immunohistochemically more often in carcinomas (50%) than in cystadenomas (29%). However, cripto staining was even more common in normal ovarian surface epithelium (80%). With all the ligands, the mucinous cystadenomas and cystadenocarcinomas were much less likely to be immunoreactive than their serous counterparts. In general, detection of both EGFR and c-erbB-2 was high with over 90% expression in all histologic categories. However, EGFR staining was noted in only half of the cystadenomas, and nearly all of the immunonegative samples were of the mucinous histologic type. Moreover, the two negative samples of c-erbB-2 among eighteen cystadenomas were of mucinous histology. Serous cystadenocarcinomas have a worse clinical prognosis than mucinous cystadenocarcinomas, and interestingly, were more likely to have EGF supergene expression. However, the staining intensity and frequency did not directly correlate to the histologic grade of serous cystadenocarcinoma, or to the severity of the patient's clinical course. In addition, the requirement of EGFR and c-erbB-2 expression for proliferation of ovarian serous cystadenocarcinoma cell lines is under examination by antisense RNA and monoclonal antibody techniques.